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Published on: February 16, 2015
Mathematical Modeling of Tumor and Cancer Stem Cells Treated with CAR-T Therapy and Inhibition of TGF-
Ellen R Swanson1, Emek Köse2, Elizabeth A Zollinger3
1Department of Mathematics, Centre College, Danville, KY, USA. ellen.swanson@centre.edu.
Abstract:
The stem cell hypothesis suggests that there is a small group of malignant cells, the cancer stem cells, that initiate the development of tumors, encourage its growth, and may even be the cause of metastases. Traditional treatments, such as chemotherapy and radiation, primarily target the tumor cells leaving the stem cells to potentially cause a recurrence. Chimeric antigen receptor (CAR) T-cell therapy is a form of immunotherapy where the immune cells are genetically modified to fight the tumor cells. Traditionally, the CAR T-cell therapy has been used to treat blood cancers and only recently has shown promising results against solid tumors. We create an ordinary differential equations model which allows for the infusion of trained CAR-T cells to specifically attack the cancer stem cells that are present in the solid tumor microenvironment. Additionally, we incorporate the influence of TGF- which inhibits the CAR-T cells and thus promotes the growth of the tumor. We verify the model by comparing it to available data and then examine combinations of CAR-T cell treatment targeting both non-stem and stem cancer cells and a treatment that reduces the effectiveness of TGF- to determine the scenarios that eliminate the tumor.
Insights
This study introduces a mathematical model for Chimeric Antigen Receptor (CAR) T-cell therapy targeting cancer stem cells in solid tumors. The model explores strategies to eliminate tumors by combining CAR T-cell treatments with TGF-β inhibition.
Area of Science:
- Mathematical Oncology
- Immunotherapy Modeling
- Cancer Stem Cell Dynamics
Background:
- The cancer stem cell hypothesis posits that a subset of cells drives tumor initiation, growth, and metastasis.
- Conventional therapies often spare cancer stem cells, leading to potential tumor recurrence.
- Chimeric Antigen Receptor (CAR) T-cell therapy, a promising immunotherapy, is expanding to solid tumors.
Purpose of the Study:
- To develop an ordinary differential equations model for CAR T-cell therapy targeting cancer stem cells in solid tumors.
- To investigate the impact of TGF-β, an immunosuppressive factor, on CAR T-cell efficacy within the tumor microenvironment.
- To identify optimal treatment strategies for tumor eradication by combining CAR T-cell approaches and TGF-β inhibition.
Main Methods:
- Construction of a mathematical model using ordinary differential equations to simulate CAR T-cell interactions with cancer stem cells and non-stem tumor cells.
- Incorporation of the inhibitory effect of TGF-β on CAR T-cell function into the model.
- Model validation against existing data, followed by in-silico examination of various treatment combinations.
Main Results:
- The model successfully simulates CAR T-cell infusion targeting cancer stem cells within the solid tumor microenvironment.
- The influence of TGF-β on CAR T-cell activity and tumor growth dynamics was quantitatively assessed.
- Simulations identified specific combinations of CAR T-cell treatments and TGF-β modulation that show potential for tumor elimination.
Conclusions:
- Mathematical modeling provides a framework for optimizing CAR T-cell therapy against solid tumors, specifically addressing the challenge of cancer stem cells.
- Targeting cancer stem cells and mitigating immunosuppressive factors like TGF-β are crucial for achieving durable responses.
- The study highlights the potential of combined therapeutic strategies for complete tumor eradication.
